Over the past decades, a large number of immunomodulatory or immunosuppressive treatments have been approved to treat central nervous system (CNS) demyelinating disorders such as multiple sclerosis (MS). Owing to the heterogeneity of patients with CNS demyelinating diseases, there is no clinical treatment that can adequately control all disease subtypes. Although significant progress has been made for relapsing-remitting MS, effective management of the progressive phase of MS has not yet been achieved. This is at least in part caused by our incomplete understanding of the mechanisms driving disease progression, despite our increasing knowledge regarding the underlying cellular and molecular mechanisms. Here, we summarized our current knowledge regarding the mechanisms of CNS demyelinating disorders and their animal models to identify open questions and challenges for existing concepts. We also discussed potential strategies for the future design of immune therapies to treat CNS demyelinating disorders.